New treatments for schizophrenia Oliver Freudenreich, MD, FACLP Co-Director MGH Schizophrenia Clinical and Research Program www.mghcme.org Disclosures I have the following relevant financial relationship with a commercial interest to disclose (recipient SELF; content SCHIZOPHRENIA): • Alkermes – Consultant honoraria (Advisory Board) • Avanir – Research grant (to institution) • Janssen – Research grant (to institution), consultant honoraria (Advisory Board) • Neurocrine – Consultant honoraria (Advisory Board) • Novartis – Consultant honoraria • Otsuka – Research grant (to institution) • Roche – Consultant honoraria • Saladax – Research grant (to institution) • Elsevier – Honoraria (medical editing) • Global Medical Education – Honoraria (CME speaker and content developer) • Medscape – Honoraria (CME speaker) • Wolters-Kluwer – Royalties (content developer) • UpToDate – Royalties, honoraria (content developer and editor) • American Psychiatric Association – Consultant honoraria (SMI Adviser) www.mghcme.org New words we learned this year Merriam-Webster • COVID-19, coronavirus, nCoV, SARS-CoV-2 • SARS-CoV, MERS-CoV • Index case, super-spreader, patient zero, contact tracing • Social distancing, self-quarantine Other • PHE, PPE, N-95 • R0 (basic reproductive number) • Hydroxychloroquine, remdesivir, convalescent serum therapy • Cordon sanitaire https://www.merriam-webster.com/words-at-play/new-dictionary-words-coronavirus-covid-19 www.mghcme.org Outline 1. Unmet needs A. Schizophrenia is a syndrome with dimensions • Refractory positive symptoms • Prominent negative symptoms* *Contributor to • Neurocognitive impairment* functional impairment B. Long-term tolerability of antipsychotics • Extrapyramidal symptoms • Weight gain C. Adherence 2. Thinking outside the box 3. Why is drug development so hard? Fellner C. Pharmacy and Therapeutics. 2017;42(2):130-134. www.mghcme.org A. SYMPTOMS www.mghcme.org Treatment-resistant schizophrenia (TRS) • Consensus guidelines on diagnosis and terminology developed by TRRIP Working Group – Clinical sub-specifiers for positive, negative, cognitive symptom domains – Time-course (i.e., early, medium, late onset) – Ultra-treatment resistant (i.e., clozapine) • Minimum requirements for TRS: – Current symptoms • Symptom threshold at least moderate severity (rating scale!) • Symptom duration at least 12 weeks • Functional impairment at least moderate (rating scale!) – Adequate treatment • At least two trials of at least 6 weeks of at least 600 CPZ-EQ • At least 80% adherence TRRIP = Treatment Response and Resistance in Psychosis Howes OD et al. Am J Psychiatry. 2017;174(3):216-229. Kane JM et al. J Clin Psychiatry. 2019 Mar 5;80(2). pii: 18com12123. [Clinical Guidance]www.mghcme.org Antipsychotic Therapeutic Drug Monitoring (TDM) • Long history in psychiatry – Lithium – Tricyclic antidepressants • Currently underutilized • Renewed interest – First guideline for TDM published by TDM taskforce of AGNP in 2004 (update 2011 and 2017) • TDM best established for CLOZ, OLANZ, HAL, FLU, PER – International consensus statement 2020* – Development of new assays for antipsychotics** AGNP = Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie Hiemke C, et al. Pharmacopsychiatry. 2018 Jan;51(1-02):e1. Horvitz-Lennon M, et al. Am J Psychiatry. 2017;174(5):421-426. *Schoretsanitis G et al. J Clin Psychiatry. 2020;81(3):19cs13169. [Consensus Statement] **https://saladax.com/saladax-biomedical-launches-clozapine-test-in-the-us-after-fda-grants-market-authorization/www.mghcme.org Lu AF35700 • Mechanism of action – Predominant D1 vs. D2 receptor antagonist • Profile comparable to clozapine – High occupancy 5-HT2A and 5-HT6 serotonin receptors • Phase III development program initiated by Lundbeck (“DayBreak” and “Debut”) – Target population: treatment-refractory schizophrenia patients – FDA fast-track designation for TRS – 6 weeks prospective treatment with olanzapine or risperidone, then 10 weeks 10 mg/20 mg or olanzapine/risperidone – Nightfall for DayBreak: no difference in PANSS total score1 – Waiting for 52-week Debut extension data ClinicalTrials.gov Identifier: NCT02717195 [DayBreak] ClinicalTrials.gov Identifier: NCT02892422 [Debut] 1https://investor.lundbeck.com/news-releases/news-release-details/lundbeck-updates-clinical-phase-iii-study-lu-af35700-treatment www.mghcme.org Cannabidiol (CBD) Non-dopamine antipsychotic? • Cannabis sativa • First case report2 – THC • Positive add-on RTC3 – CBD – 1000 mg/d CBD – Positive symptoms • PANSS -1.4, [95% CI=-2.5, - 0.2] – Cognition negative • Endocannabinoids • Negative add-on RCT4 • Anandamine* (“bliss”) – PANSS total score; MCCB 5 • CB receptors • Effects on fMRI in CHR • Biomarker 2Zuardi AW et al. J Clin Psychiatry. 1995;56:485-6. 1 3McGuire P et al. Am J Psychiatry. 2018;175(3):225-31. development 4Boggs DL et al. Psychopharmacology. 2018;235(7):1923-32. *N-arachidonoylethanolamine or AEA 5Bhattacharyya D et al. JAMA Psychiatry. 2018; 5(11):1107-17. Kopelli E et al. Psychiatry Res. 2020;291:113246. [meta-analysis] 1Minichino A et al. JAMA Psychiatry. 2019; 76(9):914-923. www.mghcme.org Pimavanserin 5-HT2A inverse agonist • Mechanism1 SSIA = Selective Serotonin Inverse Agonist – Antagonist/inverse agonist at serotonin 5HT2A receptors – Less potent antagonist/inverse agonist at 5HT2C receptors • 2016 FDA-approval for psychosis in Parkinson’s disease (Nuplazid)2,3 • Clinical case series (N=10) for TRS4 • Phase III 6-week add-on trial in (somewhat) TRS (Acadia’s ENHANCE-1)5 – Negative results for psychosis • Phase III (Acadia’s HARMONY study) for dementia- related psychosis6 1Stahl SM. CNS Spectr. 2016;21:271-5. 2Cummings J et al. Lancet. 2014;383(9916):533-40. 3Mathis MV et al. J Clin Psychiatry. 2017; 78(6):e668-e673. 4Nasrallah HA et al. Schizophr Res. 2019;208:217-220. 5ClinicalTrials.gov Identifier: NCT02970292. 6ClinicalTrials.gov Identifier: NCT03325556. www.mghcme.org Treatment-resistant schizophrenia • Non-dopaminergic drugs – Phase III by Sunovion (SEP-363856) – Mechanism of action: TAAR-1 agonism1 • Sodium benzoate augmentation – 2 positive trials • 1g/d added to antipsychotics2 • 2g/d added to clozapine3 – Mechanism of action: DAAO inhibitor 1 TAAR-1 = Trace amine-associated receptor 1 Rutigliano G et al. Front Pharmacol. 10 January 2018. 2 DAAO = D-amino acid oxidase Lane HY et al. JAMA Psychiatry. 2013;70(12):1267-1275. 3Lin CH et al. Biol Psychiatry. 2018;84(6):422-432. www.mghcme.org Symptom domains and functional outcome Negative symptoms Cognitive impairment FUNCTIONAL Positive symptoms symptoms Positive OUTCOME Antipsychotics Fervaha G et al. Acta Psychiatr Scand. 2014;130(4):290-9. Rabinowitz J et al. Schizophr Res. 2012;137(1-3):147-50. Galderisi S et al. World Psychiatry. 2014;13(3):275-87. www.mghcme.org Negative symptoms in clinical trials • Terminology and conceptualization1 – Primary versus secondary – Categorical versus dimensional – Persistent negative symptoms2 • Clinical trials methodology – Which study design should we use? – Which scale should we use? – Which dimensions are treatment-responsive? • Expressive and experiential deficits3 – Which dimensions are functionally relevant? • Avolition (motivational processes)4 1Marder SR and Galderisi S. World Psychiatry. 2017;16(1):14-24. 2Mucci A et al. Schizophr Res. 2017;196:19-28. 3Harvey PD et al. Schizophr Res. 2020;215:352-356. 4Straus GP et al. Schizophr Bull. 2020;46(4):964-970. www.mghcme.org Cariprazine for negative symptoms • Cariprazine is high-affinity D3 preferring D3/D2 partial agonist • 26-week double-blind phase III RCT – Cariprazine 3 to 6 mg/d (N=227) versus risperidone 4 mg/d (N=229) as active reference antipsychotic – Stable schizophrenia patients with prominent negative symptoms but no prominent psychosis or depression – Minimum score of 24 on the PANSS-negative factor score (NFS) • Outcome variables – Primary endpoint: PANSS-NFS – Secondary endpoint: Personal and Social Performance Scale (PSP) Nemeth G etNemeth al. Lancet. G et 2017;389(10074):1103 al. Lancet. 2017;389:1103-13.-13. www.mghcme.org PANSS-NFS change from baseline to week 26* in cariprazine for negative symptoms trial 0 -2 *Primary efficacy endpoint -4 ** p < 0.01 vs. risperidone -6 LSM = least squares mean; MMRM = Mixed-Effects Model for Repeated Improvement Measures -8 -7.4 Based on ITT population -8.9 -10 ** Broad-spectrum efficacy LSM Change from Baseline (MMRM) Baseline from Change LSM -12 Fleischhacker W. Eur Psychiatry. 2019;58:1-9. Cariprazine 3-6 mg/d (n=227) Risperidone 4 mg/d (n=229) Nemeth G et al. Lancet. 2017;389(10074):1103-13. www.mghcme.org The D3 story1 • D3 has interesting brain distribution – Limbic system (ventral striatum) and thalamus • D3 is of interest for several areas of psychiatry – Negative symptoms – Drug addiction – Mood disorders – Cognition • Interesting observation that a pure D2/3 antagonist [amisulpride] does not cause EPS – Full D3 antagonists: antipsychotic without causing EPS? – D3-preferring antipsychotic candidate F17464 under development2,3 • D3 agonist drugs [pramipexole, ropinirole; signal for aripiprazole] increased risk for pathological gambling, hypersexuality, compulsive shopping4,5 1Sokoloff P and Le Foll B. Eur J Neurosci. 2017;45:2-19. 2Slifstein M et al. Psychopharmacology. 2020;237(2):519-527. 3Bitter I et al. Neuropsychopharmacology. 2019;44(11):1917-1924 4Seeman P. Synapse. 2015;69:183-9. 5Moore TJ et al. JAMA Intern Med. 2014;174:1930www.mghcme.org-3. D2/3 Partial Agonist Antipsychotics Indications Typical dose Binding Comments range